Hippocampal abnormalities are important susceptibility factors for several human psychiatric disorders. Sensorimotor gating, assessed by prepulse inhibition of startle, is reduced in and provides a cross-species endophenotype for a group of psychiatric gating disorders, including schizophrenia, bipolar disorder, autism, and ADHD. In preliminary work, hypomorphic Sp4 mutant mice displayed vacuolization in the hippocampal dentate gyrus, reduced expression of the Grk4 gene in the hippocampus and cortex, robust deficits in sensorimotor gating and contextual memory, and decreased exploration of novel environments. The molecular, hippocampal, and behavioral abnormalities of the Sp4 mutant mice mimic several phenotypes for neuropsychiatric gating disorders. Specific Aim 1 will assess the cell autonomous roles of the Sp4 gene in the vacuolization of dentate gyrus, and the associated deficits in sensorimotor gating and contextual memory. A mouse line will be created with an inducible cre-ERT2 gene fused within the 3'UTR of the endogenous Desmoplakin (Dsp) gene by internal ribosome entry site without knocking-out Dsp expression. Tamoxifen will be used to activate the ere that in turn will reactivate or ablate the Sp4 expression in dentate granule cells. Hippocampal structural and functional abnormalities will be assessed in these rescue or conditional knockout mice. Specific Aim 2 will identify Sp4-mediated genetic pathways in the hippocampus that subserve novel object exploration. Studies will (a) further analyze the defective novelty exploration of the hypomorphic Sp4 mice in established paradigms;(b) examine whether the restoration or ablation of Sp4 expression in the dentate granule cells (Aim 1) can rescue or cause the defective novelty response. Specific Aim 3 will examine the role of the Grk4-mediated signaling pathway in the modulation of sensorimotor gating in Sp4 hypomorphic mice, using both pharmacological and genetic approaches. Cell culture experiments will examine Grk4-mediated desensitization of both dopamine D1 and mGluRI receptors in the Sp4 mutant hippocampal cells. Antagonists of dopamine D1 and mGluRI receptors will be administered to the hypomorphic Sp4 mutant mice to test for reversal of the prepulse inhibition deficit. To evaluate the disruption of Grk4-mediated GPCR signaling pathway in the modulation of sensorimotor gating and hippocampal vacuolization, double knockout mice combining the Sp4 deletion with either dopamine D1 or mGluRI receptor genes will be generated. These experiments will yield novel insights into genetic pathways within the hippocampus that underlie behavioral abnormalities relevant to several psychiatric disorders.